Method of preventing or treating benign gynaecological disorders

ABSTRACT

The present invention relates to a method of preventing or treating benign estrogen sensitive gynaecological disorders in a female mammal, wherein the method comprises the administration to said female mammal of a combination of progestogen and androgen in an amount that is therapeutically effective to prevent or reduce the symptoms of these disorders. The present method is particularly suitable for preventing or treating disorders selected from the group consisting of endrometriosis, adenomyosis, uterine fibroids, dysmenorrhoea, menorrhagia and metrorrhagia. Another aspect of the invention relates to a pharmaceutical kit comprising a plurality of oral dosage units which comprise a progestogen in an amount equivalent to 3-500 μg levonorgestrel and either 5 to 250 mg dehydroepiandrosterone or 1 to 50 mg testosterone undecanoate.

TECHNICAL FIELD

The present invention is concerned with a method of preventing ortreating benign estrogen sensitive gynaecological disorders byadministering a medicament comprising a combination of activeprinciples, said combination including a progestogen and an androgen.More particularly the present invention is concerned with a method ofpreventing or treating benign estrogen sensitive gynaecologicaldisorders, such as endometriosis, adenomyosis, uterine fibroids(leiomyomas), dysmenorrhoea, menorrhagia and metrorrhagia in femalemammals, wherein the method comprises the administration of an effectiveamount of a combination of a progestogen and an androgen.

BACKGROUND OF THE INVENTION

Endometriosis is one of the most common gynaecological disorders,affecting 10 to 15% of women in the reproductive age. It is a benigndisease defined as the presence of viable endometrial gland and stromacells outside the uterine cavity, and is most frequently found in thepelvic area. In women developing endometriosis, these endometrial cellshave the capacity to adhere to and invade the peritoneal lining, and arethen able to implant and grow. It is not known yet why some womendevelop endometriosis and others do not. The implants respond to themenstrual cycle in a similar way as the endometrium in the uterus.However, infiltrating lesions and the blood from these lesions, unableto leave the body, cause inflammation of the surrounding tissue. Themost common symptoms of endometriosis are dysmenorrhoea, dyspareunia and(chronic) abdominal pain. The occurrence of these symptoms is notrelated to the extent of the lesions. Some women with severeendometriosis are asymptomatic, while women with mild endometriosis mayhave severe pain.

Until now, no non-invasive test is available to diagnose endometriosis.Laparoscopy has to be performed to diagnose the disease. Endometriosisis classified according to the 4 stages set up by the American FertilitySociety (AFS). Stage I corresponds to minimal disease while stage IV issevere, depending on the location and the extent of the endometriosis.

Endometriosis is found in up to 50% of the women with infertility.However, currently no causal relation is known to exist between mildendometriosis and infertility. Moderate to severe endometriosis cancause tubal damage and adhesions leading to infertility.

Despite extensive research, the cause of endometriosis is still largelyunknown. Several theories for the origin of endometriosis have beenproposed, although no single hypothesis explains all cases of thedisease completely. However, the key event in all these theories is theoccurrence of retrograde menstruation.

The aims of treatment of endometriosis are pain relief, resolution ofthe endometriotic tissue and restoration of fertility (if desired). Thetwo common treatments are surgery or hormonal therapy or a combinationof both.

Surgical treatment removes the endometriotic tissue. Initially, the painrelief using this procedure approaches 70-80%. However, the pain returnsin a lot of cases because of re-growth of the endometriotic tissue. Atpresent the most permanent way to treat endometriosis is the removal ofthe ovaries, thus eliminating the production of estrogens and possibleother ovarian factors, which regulate the growth and activity of theendometriotic tissue.

The currently available pharmacological treatments of endometriosis areanti-inflammatory and hormonal. In the early stages of endometriosisnon-steroidal anti-inflammatory drugs (NSAID's) are often successful inrelieving the pelvic pain. Hormonal treatment is given mainly todown-regulate the estrogen production by the ovaries. Various drugs areavailable for suppressing this ovarian function as will be explainedbelow.

Danazol and gestrinone are both testosterone-derivatives, suppressingthe pituitary release of follicle stimulating hormone (FSH) andluteinising hormone (LH). The efficacy of these two drugs on theregression of endometriotic tissue is no better than that of otherhormonal treatments. However, both these drugs have pronouncedandrogenic side effects, like weight gain, acne and hirsutism, whichexplains the diminishing popularity of these drugs. In addition, thesedrugs produce a hypoestrogenic milieu.

Gonadotrophin releasing hormone (GnRH) agonists (e.g. nafareline,busereline) give a more complete suppression of the ovarian activity,leading to down-regulation of LH and FSH receptors. However, thisinactivity of the ovaries does not result in disappearance of theendometriosis. Several comparative randomised studies have shown thatthe efficacy of these drugs is no better than that of other existinghormonal treatments. The use of GnRH agonists is limited because thewomen taking these drugs develop hypoestrogenic symptoms, such as hotflushes, sweating, headache, vaginal dryness, and decrease in bonemineral density (BMD). Therefore these drugs can only be administeredfor a maximal period of approximately 6 months. Add-back therapy(suppletion of low doses of an estrogen, an estrogen with a progestogenor a progestogen with estrogenic activity) is sometimes given to womenreceiving GnRH agonists, to diminish the hypoestrogenic symptoms.However, it still has to be proven if treatment with GnRH agonists andadd-back therapy for more than 6 months without unwanted side effects ispossible and if such a treatment remains effective against endometriosisthroughout said period.

Progestogens have been used in a wide range of pharmaceuticalapplications for decades, including endometriosis. These drugs also workby suppressing LH and FSH and consequently induce hypoestrogenism.Examples of progestogens given for endometriosis are medroxyprogesteroneacetate, dydrogesterone and lynestrenol. These drugs are also associatedwith side-effects e.g. mood changes and breakthrough bleedings. Thetreatment of endometriosis with progestogens has not received regulatoryapproval in the United States.

Oral contraceptives, containing both an estrogen and progestogen, arealso prescribed for endometriosis. However, this treatment is notoptimal, because the stimulatory effect of the estrogenic compound inthe endometriotic lesions may not be counteracted effectively enough bythe progestogen and because the withdrawal bleeding induced also causesbleeding in endometriotic tissue.

A large percentage of women experience relief of symptoms while beingtreated with the above hormonal drugs. However, symptom recurrence islikely once the drug is discontinued. None of the aforementioned drugsis suitable for long term treatment of endometriosis, because of thesevere side-effects which are largely associated with hypoestrogenism.These treatments are therefore in most cases discontinued after a periodof 6 months after which recurrence of the symptoms is likely to occur.

It will be evident from the above that there is a great need for apharmaceutical treatment of endometriosis, which treatment may beapplied for a longer period of time than the existing hormonaltreatments, preferably until such time that the treated female reachesmenopause, and/or which treatment produces better results, particularlyin terms of side-effects during treatment and recurrence rate afterdiscontinuation of the therapy. Everything that has been said above inrelation to the treatment of endometriosis equally applies to otherbenign estrogen sensitive gynaecological disorders, notably adenomyosis,uterine fibroids, dysmenorrhoea, menorrhagia and metrorrhagia. Thesebenign gynaecological disorders are all estrogen sensitive and treatedin a comparable way as described herein before in relation toendometriosis. The available pharmaceutical treatments, however, sufferfrom the same major drawbacks as mentioned in connection withendometriosis, i.e. they have to be discontinued once the side-effectsbecome more serious than the symptoms to be treated and/or symptomsreappear after discontinuation of the therapy.

SUMMARY OF THE INVENTION

The present invention relates to a method of treatment that realises theaforementioned objectives, i.e. it can be applied in the treatment ofbenign estrogen sensitive gynaecological disorders for a significantlylonger period of time than existing medications, as it causes lessside-effects and/or offers the advantage of lower recurrence rates afterdiscontinuation than existing pharmacotherapies.

Applicants have surprisingly found that the aforementioned objectivesmay be realised by a method of treatment, which method comprisesadministration to a female mammal of a combination of a progestogen andan androgen in an amount that is therapeutically effective to prevent orreduce the symptoms of gynaecological disorders such as endometriosis,adenomyosis, uterine fibroids (leiomyomas), dysmenorrhea, menorrhagiaand metrorrhagia.

The use of androgens in the treatment of benign gynaecological disordershas not been given any serious attention so far. Nonetheless, a fewpublications can be found in both scientific and patent literature thatmention androgens in connection with e.g. endometriosis and which reporton the effect of androgens on endometrium in rats.

U.S. Pat. No. 5,753,639 describes a method for treating endometriosiscomprising administering at least one androgenic steroid having a Kivalue for the androgen receptor of less than about 2×10⁻⁸ M. Preferablysaid androgenic steroid is a synthetic progestin, especiallymedroxyprogesterone acetate.

U.S. Pat. No. 5,340,584 is concerned with methods and formulations foruse in inhibiting conception and in treating benign gynecologicaldisorders. One method disclosed in this patent comprises (a) theadministration of a GnRH composition in an amount effective to suppressovarian estrogen and progesterone production, (b) the simultaneousadministration of an estrogenic composition in an amount effective toprevent symptoms of estrogen deficiency and (c) the simultaneousadministration of a progestogen in an amount effective to decreaseendometrial cell proliferation. It is observed in the description of thepatent that in accordance with an embodiment of the invention, anandrogenic composition is administered over the first period of time inconjunction with the administration of a GnRH composition, estrogeniccomposition and progestogen. Unlike the method of treatment described inU.S. Pat. No. 5,340,584 the present method uses progestogen rather thana GnRH analogue to suppress the endocrine ovarian function. In contrastto the method described in U.S. Pat. No. 5,340,584, the presentinvention provides a method for treating benign gynaecological disorderswherein the active principles can suitably be administered orally.

Sourla et al., “Effect of Dehydroepiandrosterone on Vaginal and UterineHistomorphology in the Rat”, J. Steroid Biochem. Molec. Biol. (1998),66(3), pp. 137-149, report that following application of DHEA on thedorsal skin of ovariectomized rats the endometrium remained atrophic atall time intervals during DHEA treatment. It is concluded that the datasuggest that DHEA possesses a tissue-specific action, through its localtransformation into active estrogens in the vaginal epithelium while theuterine epithelium remains atrophic.

U.S. Pat. No. 6,284,263 describes buccal dosage units which comprise aprogestin, an estrogen and optionally an androgenic agent, as well as apolymeric carrier that bioerodes and provides for delivery of the activeagents throughout a predetermined delivery period. It is proposed in theUS-patent to employ these buccal dosage units in female hormonereplacement therapy, in female contraception and to treat female sexualdysfunction.

Although applicants do not wish to be bound by theory, it is believedthat the surprisingly good results observed for the combination of aprogestogen and an androgen are largely due to the fact that theandrogen component enhances the action of the progestogen, i.e. thesuppression of growth, proliferation and viability of endometriotictissue, adenomyosis, fibroids and endometrial tissue and/or thesuppression of undesirable side-effects of said progestogen,particularly those side-effects associated with hypo-androgenism.

The co-administration of an androgen together with a progestogen inaccordance with the present method also helps to avoid androgendeficiency. Androgen deficiency will normally result from the prolongedadministration of a progestogen (e.g. in the form of an oralcontraceptive) at the dosage levels recommended in this document. Thefact that the present method maintains serum concentrations testosteronein the physiological range, has a particularly advantageous effect onmood. Low serum androgen concentrations in females have been associatedwith feelings of discomfort. In the present method serum androgenconcentrations are maintained at a level, which is sufficiently high toprevent mood changes and feelings of discomfort.

Because androgens are precursors of estrogens, one would expectadministration of the androgen to enhance the growth, proliferation andviability of the endometriotic tissue, adenomyosis, fibroids andendometrial tissue, and thus to cause a worsening of the disease.However, surprisingly the androgen component used in accordance with thepresent invention, in contrast, has an enhancing effect on theanti-proliferative action of the progestogen on the endometrium. Theandrogen may exert this effect through activation of androgen receptors.It is known that androgen receptors are present in endometriotic andendometrial tissue as well as in adenomyosis. Horie et al.,“Immunohistochemical localisation of androgen receptor in the humanendometrium, decidua, placenta and pathological conditions of theendometrium”, Hum. Repr. vol. 7, nr. 10 (1992), pp. 1461-1466 reportthat although the proliferation and differentiation of endometrium aremediated mainly by estrogen and progesterone receptors, the androgenreceptor may play a role in modulating these changes. As yet, however,there is no scientific proof that indeed these androgen receptors play arole in the inhibition of proliferation of endometriotic tissue,adenomyosis, fibroids and endometrial tissue.

DESCRIPTION OF THE INVENTION

One aspect of the present invention is concerned with the use of acombination of active principles in the manufacture of a medicament foruse in a method of preventing or treating benign estrogen sensitivegynaecological disorders in a female mammal, wherein the medicamentcontains a progestogen and an androgen and wherein the method comprisesadministration of the medicament to said female mammal so as to providethe combination of progestogen and androgen in an amount that istherapeutically effective to prevent or reduce the occurrence of thesedisorders, in particular by inhibiting the growth, proliferation andviability of endometriotic tissue, adenomyosis, fibroids and/orendometrial tissue. Usually the present method will achieve this goal bylowering the blood serum level of endogenous 17β-estradiol to 50 pg/mlor less, preferably to less than 30 pg/ml.

The present method preferably employs essentially no gonadotrophinreleasing hormone (GnRH) analogue, meaning that if some GnRH analogue isemployed, the administered amount must remain below the level where theGnRH analogue is starting to exert a physiological effect, particularlya physiological effect on the endocrine ovarian function. Mostpreferably the present method employs no GnRH analogue at all.

The term “androgen” as used throughout this document relates to steroidsthat display androgen-like activity. Although danazol and gestrinone,components used in the treatment of endometriosis, have been referred toas androgens, they are not encompassed by the term androgens as usedthroughout this document. The term “androgen” also does not encompassprogestogens that display some androgenic activity. Examples ofprogestogens that display some androgenic activity are: gestodene,desogestrel and levonorgestrel. As regards the selectivity ratio ofprogestin-mediated effects versus androgen-mediated effects, theprogestogens employed in the present method typically exhibit aselectivity ratio of at least 0.5 (reference N. B. Sobel, Progestins inpreventive hormone therapy. Obstet Gynecol Clin North Am 21(1994), pp.299-319). Androgens always display a selectivity ratio ofprogestin-mediated effects versus androgen-mediated effects which iswell below this value.

The androgens used in the present method preferably are administered ina dosage where they exert the desired synergistic effect, but do notgive rise to significant androgenic side-effects such as acne andhirsutism, as is the case for danazol and gestrinone. Preferably theandrogen is administered in a dose which leads to an increase in bloodserum androgen level of no more than 5 nmole total testosteroneequivalent per litre, preferably less than 3 nmole total testosteroneequivalent per litre and most preferably less than 1.5 nmole totaltestosterone equivalent per litre. The total testosterone present in theserum includes both free testosterone and bound testosterone.

In order for the present method to be effective it is desirable that theadministration of the medicament, and thereby the administration of theprogestogen and androgen, occurs in an amount which is therapeuticallyeffective to suppress the endocrine ovarian function. Effectivesuppression of the endocrine ovarian function means that estrogen serumconcentrations (notably 17β-estradiol-levels) and consequentlyendogenous progesterone serum concentrations will be suppressed to sucha level that virtually no growth of endometrial tissue will occur. Whenthe ovaria are sufficiently suppressed, this will normally induceamenorrhoea. Preferably the combination of the progestogen and androgenis provided in an amount that is therapeutically effective to inhibitendometrial growth.

The medicament used in the present method may be administered in waysthat are well known in the pharmaceutical art. It was found, however,that oral, percutaneous, and intravaginal administration of themedicament are most effective. Oral administration is a particularlypreferred mode of administration as it was found to be both effectiveand very user-friendly.

The present method may successfully be applied to female mammals.Preferably these mammals include humans, cattle and pets. Mostpreferably the female mammal is a human female.

The main function of the progestogen as used in the present method is toreduce growth and proliferation of endometriotic tissue, adenomyosis,fibroids and/or endometrial tissue by suppressing the secretion ofestrogen through inhibition of the pituitary release of FSH and LH. Anunexpected advantage of the present method is the observation that thenegative mood effects and vaginal dryness normally associated with theadministration of progestogens is significantly improved by theco-administration of an androgen.

The progestogen used in the present method may suitably be selected fromthe group consisting of levonorgestrel, norgestimate, norethisterone,dydrogesterone, drospirenone, 3-beta-hydroxydesogestrel, etonogestrel(=3-keto desogestrel), 17-deacetyl norgestimate, 19-norprogesterone,acetoxypregnenolone, allylestrenol, anagestone, chlormadinone,cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone,dimethisterone, ethisterone, ethynodiol diacetate, flurogestone acetate,gastrinon, gestodene, gestrinone, hydroxymethylprogesterone,hydroxyprogesterone, lynestrenol (=lynoestrenol), medrogestone,medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone(=norethisterone), norethynodrel, norgestrel (includes d-norgestrel anddl-norgestrel), norgestrienone, normethisterone, progesterone,quingestanol,(17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-diene-20-yn-3-one,tibolone, trimegestone, algestone acetophenide, nestorone, promegestone,17-hydroxyprogesterone esters, 19-nor-17hydroxyprogesterone,17alpha-ethinyl-testosterone, 17alpha-ethinyl-19-nor-testosterone,d-17beta-acetoxy-13beta-ethyl-17alpha-ethinyl-gon-4-en-3-one oxime,precursors of these compounds capable of liberating such a progestogenwhen used in the present method and mixtures thereof.

In a preferred embodiment the progestogen is selected from the groupconsisting of levonorgestrel, norgestimate, norethisterone,drospirenone, dydrogesterone, trimegestone, dienogest, precursors ofthese progestogens and mixtures thereof.

Specific examples of progestogen precursors which may be employed inaccordance with the present invention include: anagestone acetate,chlormadinone acetate, cyproterone acetate, gestodene acetate,hydroxymethylprogesterone acetate, hydroxyprogesterone acetate,hydroxyprogesterone hexanoate, hydroxyprogesterone caproate,hydroxyprogesterone enanthate, medroxyprogesterone acetate, megestrolacetate, melengestrol acetate, nomegestrol acetate, norethindroneacetate, norethisterone acetate, norethisterone enanthate, quingestanolacetate,(17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-diene-20-yn-3-one,tibolone, algestone acetophenide, nestorone, promegestone,17-hydroxyprogesterone esters, 19-nor-17hydroxyprogesterone esters,17alpha-ethinyl-testosterone.

As mentioned before, the present method preferably employs essentiallyno GnRH analogues, i.e. GnRH agonists and/or GnRH antagonists. Examplesof GnRH agonists are: nafarelin, buserelin, leuprolin, goserelin,triptorelin, deslorelin, avorelin, histrelin. Examples of GnRHantagonists include: cetrorelix, ganirelix, abarelix, iturelix,prazarelix, antarelix, ORG 30850, HOE 2013, A-75998, A-76154, A-222509,A-198401, A-84861, Nal-Glu, D-63153, FE-200486.

The present method may suitably be used for the treatment of a varietyof benign estrogen sensitive gynaecological disorders. Such disordersinclude endometriosis, adenomyosis, uterine fibroids, dysmenorrhea,menorrhagia and metrorrhagia The present method is particularlyeffective when used in the treatment of endometriosis and adenomyosis,as the main symptoms of these disorders are directly related toendometrial proliferation. Most preferably the present method is used inthe treatment of endometriosis.

The androgen used in the present method is preferably selected from thegroup consisting of dehydroepiandrosterone (DHEA); DHEA-sulphate(DHEAS); testosterone; testosterone esters such as testosteroneundecanoate, testosterone propionate, testosterone phenylpropionate,testosterone isohexanoate, testosterone enantate, testosterone bucanate,testosterone decanoate, testosterone buciclate; methyltestosterone;mesterolon; stanozolol; androstenedione; dihydrotestosterone;androstanediol; metenolon; fluoxymesterone; oxymesterone;methandrostenolol; MENT, precursors capable of liberating theseandrogens when used in the present method and mixtures thereof. Mostpreferably the androgen is selected from the group consisting of DHEA,pharmaceutically acceptable testosterone esters such as testosteroneundecanoate, androstenedione, precursors capable of liberating theseandrogens when used in the present method and mixtures thereof.Preferably the testosterone esters employed in the present methodcomprise an acyl group which comprises at least 6, more preferably from8-20 and preferably 9-13 carbon atoms. Most preferably the androgen usedin the present method is DHEA and/or testosterone undecanoate. Theseandrogens offer the advantage that they can effectively be used in oraldosage units.

In a preferred embodiment the androgen is provided in an amountequivalent to a daily oral dosage of 5 to 250 mg DHEA, which isequivalent to a daily oral dosage of 1 to 50 mg testosteroneundecanoate. More preferably the androgen is provided in an amountequivalent to a daily oral dosage of 20 to 100 mg DHEA, most preferablyin an amount equivalent to a daily oral dosage of 40 to 60 mg DHEA. Thephrase “equivalent to a daily dosage” should not be interpretedrestrictedly. For instance, the above mentioned requirement that theadministration of the present medicament is to provide the equivalent ofa daily dosage of 5 to 250 mg DHEA, encompasses a protocol wherein DHEAis administered once a week, provided the weekly dosage is between 35and 1750 mg, i.e. such that the average daily dose is between 5 and 250mg DHEA.

The androgen used in accordance with the present invention, preferablyis not an androgenic synthetic progestin as described in U.S. Pat. No.5,753,639.

It is noted that, for instance, DHEA, testosterone undecanoate andandrostenedione are precursors of testosterone and that said precursorsper se exhibit virtually no affinity for the androgen receptors in thefemale body. The effectiveness of androgens within the method of theinvention is determined by their functionally active form, which maywell be different from the form in which they are administered.

DHEA and its sulphate ester (DHEAS) are the major secretory products ofthe human adrenal gland and collectively circulate at levels farexceeding any other steroid in the body. DHEA is a precursor for theandrogen testosterone and for the estrogenic hormones estrone andestradiol. Once DHEA is released into the body from the adrenal gland itis partly converted into the sulphate ester DHEA-S by the liver. Manytissues are able to convert DHEAS back to DHEA, which in turn can act asa precursor for testosterone, estrone and estradiol. The liver and thekidney are the principal organs involved in clearing steroid hormonesfrom the circulation. Hepatic metabolism accomplishes two functions forDHEA: a decrease in the biologic activity of the hormone, and anincrease in its water solubility, because of conversion to thehydrophilic sulphate form that can be excreted in urine.

In order to obtain the desired impact from the present method it isadvisable to administer the medicament at a dosage sufficient tomaintain serum androgen concentration of the female mammal within a(physiological) range which is equivalent to between 0.5 and 5.0,preferably to between 0.7 and 4.0, most preferably between 1.0 and 3.0nanomoles total testosterone per litre. Again, these testosteroneconcentrations include both free and bound testosterone.

In accordance with the method of the invention the medicament may beadministered at intervals which may range from 6 hours to 2 weeks.Preferably however, the medicament is administered at least once dailyas this helps to minimise fluctuations in blood serum levels of theactive principles. Most preferably the medicament is administered oncedaily. In case the medicament is administered once daily, it isadvantageous to administer the medicament in the morning, particularlybetween 6:00 a.m. and 10:00 a.m. By administering the medicament in themorning the serum concentration of the androgen will follow an almostnatural pattern, which is believed to have an advantageous effect one.g. mood.

In a particularly preferred embodiment of the invention, the methodcomprises continuous administration of the medicament for a period of atleast 3 months, preferably at least 6 months, so as to provide thecombination of the progestogen and androgen in an amount that istherapeutically effective to suppress endocrine ovarian function duringsaid period.

The term “continuous” when used in relation to the administration of oneor more active principles, means that said one or more active principlesare administered at relatively regular intervals, with no(therapeutically) significant interruptions. Naturally, minorinterruptions may occur that do not affect the overall effectiveness ofthe present method, and indeed such aberrations are encompassed by thepresent invention. In a preferred embodiment, and more arithmetically,an administration regimen is deemed to be continuous if the longestinterval between 2 subsequent administrations is not more than 3.5 timesas long as the average interval. Even more preferably said longestinterval is not more than 2.5 times as long as the average interval.

The combination of active principles used in the present method mayadvantageously also comprise an estrogen. The present method, in theabsence of co-administered estrogen, will inevitably lead to a loweringof the endogenous estrogen (17β-estradiol) levels in the female body.This lowering of blood serum estrogen levels will increase the risk ofhypoestrogenism. Hypoestrogenism is associated with a range ofundesirable symptoms such as hot flushes, vaginal dryness, osteoporosisetc. In order to prevent or suppress these symptoms it was foundadvantageous for the combination of active principles to additionallyinclude an estrogen in a therapeutically effective amount to reduce orprevent symptoms of hypoestrogenism.

The estrogen used in the present method is preferably selected from thegroup consisting of ethinyl estradiol, mestranol, quinestranol,estradiol, estrone, estran, estriol, conjugated equine estrogens,precursors capable of liberating such an estrogen when used in thepresent method and mixtures thereof. In a preferred embodiment of themethod of the invention the estrogen is selected from the groupconsisting of ethinyl estradiol, estradiol, precursors of theseestrogens and mixtures thereof. Preferably, in the present method, theestrogen is administered in an amount equivalent to a daily oral dosageof 1-40 μg ethinyl estradiol (e.g. 0,5-5 mg 17β-estradiol).

It is to be understood that the present invention not only encompassesthe use of the androgens, progestogens and estrogens specificallymentioned in this application, but also metabolites of these activeprinciples that display comparable functionality in the present method.In this context it is noted that, for instance, levonorgestrel is ametabolite of norgestimate, that estriol is a metabolite of17β-estradiol and that testosterone is a metabolite of DHEA. All thesesteroids have found application in contraceptive formulations and/orpreparations for hormone replacement therapy.

In another especially preferred embodiment of the invention the methodof treatment comprises 2 phases, a first phase of at least 30 days andat most 120 days, preferably at least 60 days and at most 90 days,during which a progestogen and no estrogen is provided, optionally inthe absence of an androgen, in an amount that is effective to suppressthe endocrine ovarian function, and a second phase of at least 3 monthsduring which the combination of a progestogen, estrogen and androgen isprovided in a daily amount effective to suppress endocrine ovarianfunction. It is a well-known fact that therapies such as the presentmethod are often discontinued because women undergoing such therapysuffer from vaginal spotting and unexpected bleeding. The 2-phase methodensures that bleeding in the form of spotting and unexpected bleeding isminimised throughout the treatment, including the initial phase.

Because the incidence of the aforementioned benign gynaecologicaldisorders drops sharply after females have reached menopause, thepresent method is particularly useful when used in the treatment ofpre-menopausal females.

A suitable dose of the progestogen may be readily identified bydetermining the lowest dose of the combination of progestogen andandrogen that is sufficient to reduce the endogenous 17β-estradiol bloodserum level of the female, within a period of 14 days, to less than 50pg/ml, preferably even less than 30 pg/ml. With reference to theexemplary progestogen levonorgestrel this dose would usually be in therange of 30 to 500 μg per day, preferably of 50 to 400 μg per day andmost preferably 100 to 300 μg per day. As will be readily understood bythose working in the field, the amount of progestogen and androgeneffective to achieve the desired results may be determined empiricallywith respect to any given progestogen and androgen and for any givenmammal. The effective dose ranges, as well as being compound specific,may also depend upon patient characteristics, such as age and weight.Further, the effective amount of the active principles also depends uponthe route of administration.

Another aspect of the present invention relates to a pharmaceutical kitcomprising a plurality of oral dosage units which comprise a progestogenin an amount equivalent to 30-500 μg levonorgestrel and 5 to 250 mgdehydroepiandrosterone and/or 1 to 50 mg testosterone undecanoate.Typically, the oral dosage units contain either dehydroepiandrosteroneor testosterone undecanoate. Preferably all the dosage units within thekit comprise the combination of a progestogen and dehydroepiandrosteroneor of a progestogen and testosterone undecanoate. The kit may suitablycomprise at least 10, more preferably at least 60 oral dosage units. Thedosage units may be in the form of e.g. tablets or capsules.

In a particularly preferred embodiment, the oral dosage units within thepresent kit contain dehydroepiandrosterone in an amount of at least 15mg, more preferably of at least 20 mg, most preferably of at least 40mg. Testosterone undecanoate is preferably contained in the presentdosage units in an amount of at least 3 mg, more preferably ot at least4 mg, most preferably of at least 8 mg. The amount ofdehydroepiandrosterone in the dosage units preferably does not exceed100 mg, more preferably it does not exceed 80 mg, most preferably itdoes not exceed 60 mg. The amount of testosterone undecanoate in thedosage units preferably does not exceed 20 mg, more preferably it doesnot exceed 16 mg, most preferably it does not exceed 12 mg.

In a preferred embodiment the present pharmaceutical kit comprises aplurality of oral dosage units comprising a progestogen in an amountequivalent to 50-400 μg, preferably 100-300 μg levonorgestrel and 20 to100 mg, preferably 40 to 60 mg dehydroepiandrosterone.

In yet another preferred embodiment the aforementioned plurality of oraldosage units additionally contain an estrogen in an amount equivalent to1 to 40 μg ethinyl estradiol.

Preferably said estrogen is selected from the group consisting ofethinyl estradiol and 17β-estradiol. Most preferably the estrogen isethinyl estradiol.

The invention is further illustrated by means of the following examples.

EXAMPLES Example 1

The effects on endometrium of the progestogen levonorgestrel and theandrogen testosterone were determined in rabbits according to the methodof McPhail (Mc Phail M. K. “The assay of progestin” J Physiol (1934),83, 145-156). Four groups of each 5 rabbits were pretreated with dailysubcutaneous dosages of 5 μg 17β-estradiol for 6 days.

After pretreatment, 3 groups either received levonorgestrel at an oraldose of 8 μg per day for 5 days, testosterone in a subcutaneous dose of20 mg per day for 5 days, or levonorgestrel and testosterone together inthe aforementioned routes and doses for 5 days. The fourth group wasused as the negative control.

Autopsy was performed after the treatment period and the uterus wasweighed and histological sections were prepared from each uterine hornand these were microscopically evaluated according to the McPhail Index(scores 0-4; 0=no differentiation; 4=maximal differentiation).

The pre-treatment phase induced proliferation of the endometrium. In thesecond phase, when the study compounds were administered, the degree ofendometrial differentiation (transformation) was investigated. Thelevonorgestrel group showed a McPhail index of 2.1±0.4, while thetestosterone only group had a McPhail index of 2.9±0.1. Whenlevonorgestrel and testosterone were given together a McPhail index of3.7±0.2 was observed. Thus, significantly more differentiation of theendometrium was observed when levonorgestrel and testosterone were giventogether compared to the groups only receiving levonorgestrel ortestosterone, indicating that progestogen and androgen have an additivetransforming effect on endometrial tissue. No firther proliferation ofthe endometrium was observed in any of the treatment groups in thesecond phase of the McPhail study. This reflects the anti-proliferativeeffect of progestogen and androgen on endometrial tissue. In thissetting it was presumed that the effect of the study compounds on theendometrial tissue is indicative of the effect on endometriotic tissue.This is a reasonable presumption because this latter tissue isessentially identical to endometrial tissue.

Example 2

A clinical study is conducted in 200 healthy young women. Four groups of50 women, who use a combined oral contraceptive containing at least 30microgram ethinyl estradiol for at least 19 days before the start of thestudy, receive a daily oral dose of 20 microgram ethinyl estradiol and100 microgram levonorgestrel, or 30 microgram ethinyl estradiol and 150microgram levonorgestrel, either with or without 50 mg DHEA for 104 days(15 weeks) without pauses. Vaginal spotting and bleeding is scored dailyby the participants in a diary and the effects on general well being arescored at baseline and at each study visit (every 5 weeks during studydrug administration) on a psychometric rating scale. The psychometricrating scale used is especially suited for identifying differences in apopulation of healthy young women. The scale is a 24-item (placid,sleepy, jittery, intense, lacking confidence, energetic, sensitive,tired, well-balanced, at-rest, drowsy, fearful, lively, sickly, in agood mood, irritable, lethargic, quiet, full-of-pep, optimistic, moody,active, tense, sad), 4-point (yes, definitely; yes, a bit; no, in factnot; no, definitely not) scale to be scored by the woman herself. Inaddition, endocrine measurements are performed in a subgroup of theparticipants (17β-estradiol, progesterone, total testosterone, LH, FSHand SHBG).

Results show that in the groups of women receiving DHEA less vaginalbreakthrough spotting and bleeding is reported and generally betterscores are obtained on items in the domain of energy (viz. tired,drowsy, energetic, placid and lethargic) and less side effects occurthan in those women not receiving it. In addition, in the participantsreceiving DHEA significantly higher testosterone levels are seen whichare well within the physiological range.

Example 3

A clinical study is conducted in 100 healthy young women. Two groups of50 women, who use a combined oral contraceptive containing at least 30microgram ethinyl estradiol for at least 19 days before the start of thestudy, receive a daily oral dose of 3 mg 17β-estradiol and 1.5 mgnorethisterone acetate either with or without 50 mg DHEA for. 104 days(15 weeks) without pauses. Vaginal spotting and bleeding is scored dailyby the participants in a diary. The effects on general well being arescored at baseline and at each study visit (every 5 weeks during studydrug admninistration) using the psychometric rating scale described inexample 2.

Ovulation inhibition is investigated by analysing pregnanediol samplestwice a week during 4 weeks between week 7 and 14. In addition,endocrine measurements are performed in a subgroup of the participants(17β-estradiol, progesterone, total testosterone, LH, FSH and SHBG).

Again results show that in the groups of women receiving DHEA lessvaginal breakthrough spotting and bleeding is reported and generallybetter scores are seen on items in the domain of energy (viz. tired,drowsy, energetic, placid and lethargic) and less side effects occurthan in those women not receiving it. In addition, in the participantsreceiving DHEA significantly higher testosterone levels are seen whichare well within the physiological range. Although the number ofparticipants is small, both regimens appear to suppress ovulationconsistently.

1-16. (canceled)
 17. A method of preventing or treating benign estrogensensitive gynaecological disorders in a female mammal, said methodcomprising administering to said female mammal a combination ofprogestogen and androgen in an amount that is therapeutically effectiveto prevent or reduce the symptoms of these disorders, the androgen beingprovided in an amount equivalent to a daily oral dosage of 5 to 100 mgdehydroepiandrosterone (DHEA).
 18. The method according to claim 17,wherein the combination of the progestogen and androgen is provided inan amount that is therapeutically effective to suppress the endocrineovarian function.
 19. The method according to claim 17, wherein thecombination of active principles additionally comprises an estrogen in atherapeutically effective amount to reduce or prevent symptoms ofhypoestrogenism.
 20. The method according to claim 17, wherein themethod comprises oral administration of the medicament.
 21. The methodaccording to claim 17, wherein the benign estrogen sensitivegynaecological disorder is selected from the group consisting ofendometriosis, adenomyosis, uterine fibroids, dysmenorrhea, menorrhagiaand metrorrhagia.
 22. The method according to claim 17, wherein thecombination of progestogen and androgen is administered in an amountthat is sufficient to reduce the endogenous 17β-estradiol blood serumlevel of the female, within a period of 14 days, to less than 50 pg/ml.23. The method according to claim 17, wherein the progestogen isadministered in an amount which is equivalent to a daily oral dosage of30 to 500 μg levonorgestrel.
 24. The method according to claim 17,wherein the androgen is selected from the group consisting ofdehydroepiandrosterone, testosterone undecanoate, precursors capable ofliberating these androgens when used in the present method and mixturesthereof.
 25. The method according to claim 17, wherein the androgen isprovided in an amount equivalent to a daily oral dosage of 20 to 100 mgdehydroepiandrosterone.
 26. The method according to claim 17, whereinthe medicament is administered at a dosage sufficient to maintain serumandrogen concentration of the female mammal at a level equivalent tobetween 0.5 and 5.0 nanomoles total testosterone per litre.
 27. Themethod according to claim 17, wherein the method comprises at least oncedaily administration of the medicament.
 28. The method according toclaim 17, wherein the method comprises continuous administration of themedicament for a period of at least 3 months so as to provide thecombination of progestogen and androgen in an amount that istherapeutically effective to suppress ovarian function during saidperiod.
 29. The method according to claim 28, wherein the methodcomprises 2 phases, a first phase of at least 30 days and at most 120days during which progestogen and no estrogen is provided, optionally inthe absence of the androgen, in an amount that is effective to suppressendocrine ovarian function, and a second phase of at least 3 monthsduring which the combination of progestogen, estrogen and the androgenis provided in a daily amount effective to suppress endocrine ovarianfunction.
 30. A pharmaceutical kit comprising a plurality of oral dosageunits which comprise a progestogen in an amount equivalent to 30-500 μglevonorgestrel and 20 to 100 mg dehydroepiandrosterone.
 31. Thepharmaceutical kit according to claim 30, wherein the kit comprises aplurality of oral dosage units comprising a progestogen in an amountequivalent to 50-400 μg levonorgestrel and 40 to 60 mgdehydroepiandrosterone.
 32. The pharmaceutical kit according to claim30, wherein the plurality of oral dosage units additionally contains anestrogen in an amount equivalent to 1 to 40 μg ethinyl estradiol.